Palladium-catalyzed copper-free sonogashira coupling reaction in water and acetone

Article abstract of DOI:10.1055/s-2007-984533

An efficient palladium-catalyzed copper-free Sonogashira reaction in water and acetone has been developed under mild conditions. The results showed that the aryl iodides could carry out the cross-coupling reaction with a variety of terminal alkynes in high yields in water-acetone in the absence of amine, copper(I) salts, or phosphine ligands at 60°C for one hour, and good yields were obtained for aryl bromides at 60°C for 12-24 hours in the presence of triphenylphosphine and piperidine. The method could be used to synthesize polyethynyl aromatic compounds in a one-pot reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984533

LETTER
1843
Palladium-Catalyzed Copper-Free Sonogashira Coupling Reaction in Water
and Acetone
Copper-Free
S
h
onogashira
C
e
oupling R
n
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953244; E-mail: yhzhang@zjuem.zju.edu.cn
Received 11 April 2007
Initially, we chose the coupling of 1-iodo-4-methoxy-
Abstract: An efficient palladium-catalyzed copper-free Sono-
gashira reaction in water and acetone has been developed under
mild conditions. The results showed that the aryl iodides could carry
out the cross-coupling reaction with a variety of terminal alkynes in
benzene (1 mmol) and 1-ethynylbenzene (1.5 mmol) as
the model reaction to study the Sonogashira reaction in
water in the absence of copper and phosphine ligands. The
high yields in water–acetone in the absence of amine, copper(I) reaction was carried out under different conditions for one
salts, or phosphine ligands at 60 °C for one hour, and good yields
hour using 1 mol% Pd(OAc)2 as the catalyst and the
were obtained for aryl bromides at 60 °C for 12–24 hours in the
results were summarized in Table 1. It was found that the
presence of triphenylphosphine and piperidine. The method could
reaction was sluggish in pure acetone (Table 1, entry 1).
be used to synthesize polyethynyl aromatic compounds in a one-pot
However, the reaction rate was significantly promoted by
reaction.
the addition of water and an optimum yield was achieved
Key words: copper-free, palladium-catalyzed, Sonogashira cou-
when the amount of water to acetone was 3 g to 3 g (Table
pling, aqueous
1, entries 2–4). Phase-transfer agents and ionic liquids like
PEG 2000, [bmim]BF4, and [bmim]PF6 gave poor yields
when used in a mixture with water (Table 1, entries 5–7).
The Sonogashira reaction via the coupling of terminal
Among the bases tested, Na2CO3, K2CO3, K3PO4, Et3N,
alkynes with aryl or alkenyl halides has provided a pow-
and piperidine gave poor yields (Table 1, entries 9–13),
erful synthetic tool in organic chemistry and constitutes
while high yields were obtained with strong bases such as
the key step in the preparation of many natural products
NaOH and KOH (Table 1, entries 3 and 8). Raising or
and functionalized materials.1,2 Generally, the Sonogash-
lowering the reaction temperature did not improve the
ira reaction is performed in the presence of palladium
yield (Table 1, entries 14 and 15).
complex and copper salts using a variety of ligands in or-
ganic solvents.3,4 However, copper salts can induce the
homocoupling of the terminal alkynes when the reaction
is exposed to air or oxidants,5 and thus lead to low yields
of desired products and separation problems. Recently,
copper-free Sonogashira reaction has been developed and
good results were achieved,6–11 which include the use of
other metal co-catalysts,8 special reaction techniques,9,10
and special ligands.11
We next explored the scope and limitation of this aqueous
catalytic system for different substrates.15 A variety of the
aryl iodides were subjected to the conditions and the
results were summarized in Table 2. The yields were gen-
erally high after one hour for both electron-rich and elec-
tron-deficient aryl iodides and all of the products were
easily separated by the extraction with diethyl ether
(Table 2, entries 1–11). In the reaction of 1-bromo-4-
iodobenzene with phenylacetylene, 1,4-biphenyl-ethynyl-
benzene was isolated as a byproduct, and 1-bromo-4-
phenylethynyl benzene was obtained in a moderate yield
(Table 2, entry 7), but excellent yield and selectivity was
afforded when using 1-chloro-4-iodobenzene as the sub-
strate (Table 2, entry 8). The hydrolysis of 4-iodobenzo-
nitrile lowered the desired coupling yield (Table 2, entry
10) and no coupling product was obtained with ethyl 4-
iodobenzoate. Excellent yield was obtained for 1-iodo-
naphthalene (Table 2, entry 6). It is worth mentioning that
the catalytic system could tolerate a broad range of func-
tional groups, such as OMe, OH, NH2, and COMe, NO2.
The coupling of various terminal alkynes delivered the
products with high yields (Table 2, entries 12–20).
The development of transition-metal-catalyzed reactions
in aqueous solvent system has aroused much interest due
to the economical and environmental reasons.12 The palla-
dium–copper-catalyzed Sonogashira reaction in aqueous
media has been applied in the synthesis of biomolecules
using aqueous soluble phosphine ligands.13 Very recently,
Yang et al. reported an elegant copper-free Sonogashira
reaction in water, but only examples of aryl iodides were
given and the reaction time was relatively long (around 24
h).13h In accordance with our research program on the
catalytic reactions in aqueous phase, we have studied the
effects of water on the palladium-catalyzed coupling reac-
tions.14 In this paper, we report the results of Sonogashira
coupling reactions in water and acetone without copper
salts.
In the case of aryl bromides, the catalytic system present-
ed low activity and only a 38% yield was obtained for the
activated 1-bromo 4-nitrobenzene (Table 2, entry 21).
Trace of the coupling product was observed with bro-
mobenzene. In order to optimize the performance for aryl
SYNLETT 2007, No. 12, pp 1843–1850
2
4
.0
7
.2
0
0
7
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984533; Art ID: W07307ST
© Georg Thieme Verlag Stuttgart · New York

1844
S. Shi, Y. Zhang
LETTER
bromides in water–acetone, we examined the Sonogashira 1-Bromo-4-chlorobenzene reacted with phenylacetylene
reaction of 1-(4-bromophenyl)ethanone and phenyl- gave 1-chloro-4-(2-phenylethynyl)benzene as the only
acetylene in the presence of 10 mol% PPh3 under various product, thus showing a good selectivity (Table 3, entry
reaction conditions. It was found that a combination of 5 8). The coupling reaction of 1-bromonaphthalene and
mol% PdCl2 and 2 equivalents piperidine gave the best bromoheteroaryl delivered moderate to good yields after
isolated yield of 84% at 60 °C for 12 hours (Table 3, entry the reaction time was prolonged to 24 hours (Table 3, en-
7). This optimized reaction conditions were applicable to tries 12–16). The hydrolysis of groups such as CN and
a range of aryl bromides.16 As presented in Table 3, high CO2Et was suppressed markedly in this catalytic system
yields were afforded for the electron-deficient aryl and good coupling yields were obtained (Table 3, entries
bromides (Table 3, entries 1–8), but longer reaction time 4–6, 19, 20). Unfortunately, the catalytic system was in-
was required for the electron-rich aryl bromides (Table 3, active for aryl chlorides (Table 3, entries 21 and 22).
entries 10, 11).
Table 1 Effect of Solvent, Base, and Temperature on the Sonogashira Reactiona
1 mol% Pd(OAc)2
O
I
O
+
base, 1 h
H2O–acetone
Entry
1
Solvent (g:g)
Base
Temp (°C)
Conv. (%)
Yield (%)b
acetone–H2O (6:0)
acetone–H2O (4:2)
acetone–H2O (3:3)
acetone–H2O (2:4)
H2O–PEG2000 (3:3)
H2O–[bmim]BF4 (3:3)
H2O–[bmim]PF6 (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
acetone–H2O (3:3)
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
60
60
60
60
60
60
60
60
60
60
60
60
60
50
80
10
42
100
63
50
0
10
38
87
53
50
0
2
3
4
5
6
7
3
3
8
100
14
32
83
27
58
94
71
88
14
32
74
27
38
83
53
9
Na2CO3
K2CO3
K3PO4
Et3N
10
11
12
13
14
15
piperidine
NaOH
NaOH
a Reaction conditions: 1-iodo-4-methoxybenzene (1 mmol), phenylacetylene (1.5 mmol), base (2 mmol).
b GC yield based on the amount of 1-iodo-4-methoxybenzene used.
Table 2 Sonogashira Reaction of Aryl Iodides with Terminal Alkynesa
1 mol% Pd(OAc)2
R1
R2
R1
I
R2
+
NaOH, 60 °C, 1 h
H2O–acetone
Entry
1
R1
Alkyne
Product
Yield (%)b
83
O
4-OMe
4-OH
a
a
2
91
HO
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LETTER
Copper-Free Sonogashira Coupling Reaction
1845
Table 2 Sonogashira Reaction of Aryl Iodides with Terminal Alkynesa (continued)
1 mol% Pd(OAc)2
R1
R2
R1
I
R2
+
NaOH, 60 °C, 1 h
H2O–acetone
Entry
3
R1
Alkyne
Product
Yield (%)b
88
4-NH2
4-Me
H
a
a
a
H2N
4
5
98
90
6
1-Naph
a
99
7
8
4-Br
a
a
a
a
a
68
91
90
66
93
Br
4-Cl
Cl
O
9
4-COMe
4-CN
4-NO2
10
11
NC
O2N
O
12
13
14
15
4-OMe
4-OMe
4-OMe
H
92
85
50
84
b
c
O
O
OH
HO
d
b
16
17
H
H
c
83
75
HO
d
O2N
18
4-NO2
b
85
19
20
4-NO2
4-NO2
c
99
94
O2N
O2N
HO
d
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1846
S. Shi, Y. Zhang
LETTER
Table 2 Sonogashira Reaction of Aryl Iodides with Terminal Alkynesa (continued)
1 mol% Pd(OAc)2
R1
R2
R1
I
R2
+
NaOH, 60 °C, 1 h
H2O–acetone
Entry
21
R1
Alkyne
Product
Yield (%)b
a
a
a
38c
O2N
Br
O2N
22
23
Tracec
0c
Br
O
O
Br
a Reaction conditions: aryl halide (1 mmol), terminal alkyne (1.2 mmol), 1 mol% Pd(OAc)2, NaOH (2 mmol), H2O–acetone = 3:3 g, 60 °C (bath
temperature), 1 h.
b Isolated yields.
c 6 h.
Table 3 The Coupling of Aryl Bromides with Terminal Alkynesa
PdCl2, PPh3, piperidine
R1
Br
+
R2
R1
R2
H2O–acetone, 60 °C
Entry
Bromide
Alkyne
Time (h)
12
Yield (%)b
85
1
2
O2N
Br
a
a
Br
12
12
94
86
O2N
Br
NO2
3
a
4
5
a
a
12
12
95
83
EtOOC
NC
Br
Br
Br
6
7
a
a
12
12
90
84
NC
O
Br
Br
8
9
a
a
a
a
24
24
24
24
80
Cl
52
Br
10
11
61c
67c
Br
O
Br
Synlett 2007, No. 12, 1843–1850 © Thieme Stuttgart · New York

LETTER
Copper-Free Sonogashira Coupling Reaction
1847
Table 3 The Coupling of Aryl Bromides with Terminal Alkynesa (continued)
PdCl2, PPh3, piperidine
R1
Br
+
R2
R1
R2
H2O–acetone, 60 °C
Entry
Bromide
Alkyne
Time (h)
24
Yield (%)b
58c
Br
12
a
13
14
15
16
a
a
a
a
24
12
12
12
77
66
85
53
Br
Br
N
N
Br
S
Br
S
17
18
12
12
70
72
O2N
O2N
Br
b
OH
Br
d
a
19
20
21
22
1
1
91
EtOOC
NC
I
a
a
a
87
I
48
48
42
O2N
Cl
Trace
Cl
a Reaction conditions: aryl halide (1 mmol), terminal alkyne (1.2 mmol), 5 mol% PdCl2, 10 mol% PPh3, piperidine (2 mmol), H2O–
acetone = 3:3 g, 60 °C (bath temperature), N2.
b Isolated yield.
c Terminal alkyne (1.5 mmol).
Table 4 Coupling of Dihaloaryls and Polyhaloaryls with Terminal Alkynesa
Entry
1
Halide
Alkyne
Time (h)
24
Product
Yield (%)b
83
I
Br
a
a
Br
2
24
74
I
Synlett 2007, No. 12, 1843–1850 © Thieme Stuttgart · New York

1848
S. Shi, Y. Zhang
LETTER
Table 4 Coupling of Dihaloaryls and Polyhaloaryls with Terminal Alkynesa (continued)
Entry
Halide
Alkyne
Time (h)
Product
Yield (%)b
Br
3
a
24
64
I
4
5
a
a
24
24
51
47
Br
Br
Br
Br
Br
Br
6
a
48
58c
Br
Br
Br
Br
7
a
a
48
46d
Br
8
9
48
48
78
68
N
Br
N
Br
Br
N
I
e
N
N
a Reaction conditions: dihalide (1 mmol), terminal alkyne (2.4 mmol), 10 mol% PdCl2, 20 mol% PPh3, piperidine (4 mmol),
H2O–acetone = 3:3 g, 60 °C (bath temperature), N2.
b Isolated yield.
c Reaction conditions: trihalide (1 mmol), terminal alkyne (3.6 mmol), 15 mol% PdCl2, 30 mol% PPh3, piperidine (6 mmol),
H2O–acetone = 3:3 g, 60 °C (bath temperature), N2.
d Reaction conditions: tetrahalide (1 mmol), terminal alkyne (4.8 mmol), 20 mol% PdCl2, 40 mol% PPh3, piperidine (8 mmol),
H2O–acetone = 3:3 g, 60 °C (bath temperature), N2.
The PdCl2–PPh3–H2O–acetone catalytic system was also optoelectronic devices.17 It can be seen that the use of 10
utilized to synthesize the polyethynyl aromatic com- mol% PdCl2 and 20 mol% PPh3 at 60 °C delivered the bi-
pounds (Table 4), which have currently attracted much at- ethynylaryls as the main products (Table 4, entries 1–5).16
tention because of their potential applications in various More PdCl2 and PPh3 were required for tribromo- and
Synlett 2007, No. 12, 1843–1850 © Thieme Stuttgart · New York

LETTER
Copper-Free Sonogashira Coupling Reaction
1849
1713. (g) Heuze, K.; Mery, D.; Gauss, D.; Blais, J. C.;
Astruc, D. Chem. Eur. J. 2004, 10, 3936.
(8) (a) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M. Org.
Lett. 2000, 2, 2935. (b) Eberhard, M. R.; Wang, Z.; Jensen,
C. M. Chem. Commun. 2002, 818. (c) Sakai, N.; Annaka,
K.; Konakahara, T. Org. Lett. 2004, 6, 1527.
tetrabromobenzene (Table 4, entries 6 and 7). In the reac-
tion of 2,6-dibromopyridine, 2,6-biethynyl pyridine was
afforded in 78% yield (Table 4, entry 8). Ethynylation of
bromoiodobenzene with 2-ethynyl pyridine gave the
desired product in 68% yield (Table 4, entry 9).
(9) (a) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691. (b) Park, S. B.; Alper, H.
Chem. Commun. 2004, 1306. (c) Gholap, A. R.;
In summary, we have developed a copper-free Sono-
gashira reaction in aqueous media under mild reaction
conditions. The catalytic system tolerates a range of
groups, including the unprotected hydroxy and amino
groups. The high efficiency and easy separation of the
products make the method attractive and viable in
aqueous media.
Venkatesan, K.; Pasricha, R.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J. Org. Chem. 2005, 70, 4869.
(10) (a) Djakovitch, L.; Rollet, P. Adv. Synth. Catal. 2004, 346,
1782. (b) Rollet, P.; Kleist, W.; Dufaud, V.; Djakovitch, L.
J. Mol. Catal. A: Chem. 2005, 241, 39. (c) Li, P.; Wang, L.
Adv. Synth. Catal. 2006, 348, 681. (d) Elizabeth, T.; Ali, A.;
Julien, M. Synlett 2005, 487. (e) Cwik, A.; Hell, Z.;
Figueras, F. Tetrahedron Lett. 2006, 47, 3023.
Acknowledgment
(11) (a) Böhm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem.
2000, 3679. (b) Kollhofer, A.; Pullmann, T.; Plenio, H.
Angew. Chem. Int. Ed. 2003, 42, 1056. (c) Gelman, D.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2003, 42, 5993.
(d) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer,
P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191. (e) Ma, Y.;
Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu, X.; Andrus, M.
B. Org. Lett. 2003, 5, 3317. (f) Cheng, J.; Sun, Y.; Wang,
F.; Guo, M.; Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org. Chem.
2004, 69, 5428.
(12) (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997. (b) Organic Synthesis in
Water; Grieco, P. A., Ed.; Academic Press: Dordrecht,
1997. (c) Aqueous-Phase Organometallic Catalysis, 2nd ed;
Cornils, B.; Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 2004. (d) Leadbeater, N. E. Chem. Commun.
2005, 2881. (e) Li, C.-J. Chem. Rev. 2005, 105, 3095.
(13) (a) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc.
1990, 112, 4324. (b) Dibowski, H.; Schmidtchen, F. P.
Tetrahedron Lett. 1998, 39, 525. (c) Novak, Z.; Szabo, A.;
Repasi, J.; Kotschy, A. J. Org. Chem. 2003, 68, 3327.
(d) Djakovitch, L.; Rollet, P. Tetrahedron Lett. 2004, 45,
1367. (e) Bhattacharyaa, S.; Sengupta, S. Tetrahedron Lett.
2004, 45, 8733. (f) Wolf, C.; Lerebours, R. Org. Biomol.
Chem. 2004, 2, 2161. (g) Gelman, D.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2005, 44, 6173. (h) Liang, B.; Dai,
M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391.
(i) Zhang, G. Synlett 2005, 619.
We thank the support of Natural Science Foundation of China (No.
20571063).
References and Notes
(1) (a) Viehe, H. G. Chemistry of Acetylene; Marcel Dekker:
New York, 1969, 597. (b) Bohlmann, F.; Burkhart, F. T.;
Zero, C. Naturally Occurring Acetylenes; Academic Press:
London / New York, 1973. (c) Sonogashira, K. In
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 551.
(d) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 1998.
(e) Miyaura, N. Cross-Coupling Reaction; Springer: Berlin,
2002.
(2) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004,
104, 3079. (b) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 4176. (c) Tykwinski, R. R. Angew. Chem. Int. Ed.
2003, 42, 1566.
(3) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 44, 4467. (b) Dieck, H. A.; Heck, R. F.
J. Organomet. Chem. 1975, 93, 259. (c) Cassar, L.
J. Organomet. Chem. 1975, 93, 253.
(4) (a) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
(b) Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y.
J. Org. Chem. 2001, 66, 1910. (c) Batey, R. A.; Shen, M.;
Lough, A. J. Org. Lett. 2002, 4, 1411. (d) Eckhardt, M.; Fu,
G. C. J. Am. Chem. Soc. 2003, 125, 13642. (e) Novak, Z.;
Szabo, A.; Repasi, J.; Kotschy, A. J. Org. Chem. 2003, 68,
3327. (f) Garcia, D.; Cuadro, A. M.; Alvarez-Builla, J.;
Vaquero, J. J. Org. Lett. 2004, 6, 4175. (g) Kollhofer, A.;
Plenio, H. Adv. Synth. Catal. 2005, 347, 1295. (h) Posset,
T.; Blumel, J. J. Am. Chem. Soc. 2006, 128, 8394.
(5) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem.
Int. Ed. 2000, 39, 2632.
(6) (a) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett.
2003, 44, 8653. (b) Urgaonkar, S.; Verkade, J. G. J. Org.
Chem. 2004, 69, 5752. (c) Li, J.-H.; Liang, Y.; Xie, Y.-X. J.
Org. Chem. 2005, 70, 4393. (d) Li, J.-H.;Zhang, X.-D.;Xie,
Y.-X. Synthesis 2005, 804. (e) Liang, Y.; Xie, Y.-X.; Li, J.-
H. J. Org. Chem. 2006, 71, 379.
(7) (a) Alonso, D. A.; Najera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365. (b) Najera, C.; Gil-Molto, J.;
Karlstrom, S.; Falvello, L. R. Org. Lett. 2003, 5, 1451.
(c) Méry, D.; Heuzé, K.; Astruc, D. Chem. Commun. 2003,
1934. (d) Heuze, K.; Mery, D.; Gauss, D.; Astruc, D. Chem.
Commun. 2003, 2274. (e) Arques, A.; Auñon, D.; Molina, P.
Tetrahedron Lett. 2004, 45, 4337. (f) Alonso, D. A.;
Botella, L.; Najera, C.; Pacheco, M. C. Synthesis 2004,
(14) (a) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70,
6122. (b) Liu, L.; Zhang, Y.; Xin, B. J. Org. Chem. 2006, 71,
3994. (c) Xin, B.; Zhang, Y.; Liu, L.; Wang, Y. Synlett 2005,
3083. (d) Xin, B.; Zhang, Y.; Cheng, K. J. Org. Chem. 2006,
71, 5725.
(15) General Procedure for the Sonogashira Reaction of Aryl
Iodides
A mixture of NaOH (0.08 g, 2 mmol), Pd(OAc)2 (2 mg, 1
mol%), distilled H2O (3 g), and acetone (3 g, 3.8 mL) was
stirred for 5 min. Then, aryl iodides (1 mmol) and terminal
alkynes (1.2 mmol) were introduced and the mixture of the
reaction was heated to 60 °C for 1 h. Afterward, the reaction
solution was cooled to r.t. and extracted four times with Et2O
(4 × 10 mL). The combined organic phase was analyzed by
GC and GC-MS. Further purification of the product was
achieved by flash chromatography on a silica gel column.
1-(2-Phenylethynyl)naphthalene (Table 2, entry 6): 1H
NMR (500 MHz, CDCl3, TMS): d = 8.43–8.45 (d, 1 H,
J = 8.35 Hz), 7.72–7.80 (m, 3 H), 7.61–7.63 (m, 2 H), 7.55
(m, 1 H), 7.46–7.48 (m, 1 H), 7.33–7.38 (m, 1 H), 7.30–7.32
(m, 3 H). MS (EI): m/z (%) = 229 (20) [M+ + 1], 228 (100)
[M+], 226 (43).
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S. Shi, Y. Zhang
LETTER
(16) General Procedure for the Sonogashira Reaction of Aryl
Bromides and Polyhaloaryls
the reaction solution was cooled to r.t. and extracted with
Et2O (4 × 10 mL). The combined organic phase was
analyzed by GC and GC–MS. Further purification of the
product was achieved by flash chromatography on a silica
gel column.
A mixture of piperidine (0.17 g, 2 mmol; for dihalides, 4
mmol; for trihalides, 6 mmol; for tetrahalides, 8 mmol),
PdCl2 (11 mg, 5 mol%; for dihalides, PdCl2 = 10 mol%; for
trihalides, PdCl2 = 15 mol%; for tetrahalides, PdCl2 = 20
mol%), PPh3 (26 mg, 10 mol%; for dihalides, PPh3 = 20
mol%; for trihalides, PPh3 = 30 mol%; for tetrahalides,
PPh3 = 40 mol%), distilled H2O (3 g), and acetone (3 g, 3.8
mL) was stirred for 5 min under nitrogen. Then, aryl
bromides or polyhaloaryls (1 mmol) and terminal alkynes
(1.2 mmol; for dihalides, alkynes = 2.4 mmol; for trihalides,
alkynes = 3.6 mmol; for tetrahalides, alkynes = 4.8 mmol)
were introduced and the mixture of the reaction was heated
to 60 °C for the indicated time under nitrogen. Afterwards,
1,4-Bis(2-phenylethynyl)benzene (Table 4, entry 1): 1H
NMR (500 MHz, CDCl3, TMS): d = 7.52–7.54 (m, 4 H),
7.50 (s, 4 H), 7.34–7.36 (m, 6 H). MS (EI): m/z (%) = 279
(25) [M+ + 1], 278 (100) [M+], 139 (10).
(17) (a) Yamaguchi, Y.; Kobayashi, S.; Miyamura, S.; Okamoto,
Y.; Wakamiya, T.; Matsubara, Y.; Yoshida, Z. Angew.
Chem. Int. Ed. 2004, 43, 366. (b) Yamaguchi, Y.; Ochi, T.;
Miyamura, S.; Tanaka, T.; Kobayashi, S.; Wakamiya, T.;
Matsubara, Y.; Yoshida, Z.-I. J. Am. Chem. Soc. 2006, 128,
4504.
Synlett 2007, No. 12, 1843–1850 © Thieme Stuttgart · New York

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